CovidEP: Therapeutic Plasma Exchange to Alleviate Hyperinflammatory Condition During Severe Covid-19 Infections

Sponsor

Hospices Civils de Lyon (Other)

Overall Status

Recruiting

CT.gov ID

NCT04751643

Collaborator

(none)

132

Enrollment

Locations

Arms

19.4

Anticipated Duration (Months)

14.7

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Severe Covid-19 (Coronavirus Disease 2019) infections generate major but inappropriate production of cytokines and, in some cases, generate anti-IFN (Interferon) auto-antibodies, inducing acute respiratory distress syndrom (ARDS). Therapeutic plasma exchange (TPE) have been reported to be efficient for improving the hyperinflammatory condition state and the respiratory function, which has been described in case reports or small series.

The study aims to remove cytokines during cytokine storm and anti-IFN auto-antibodies (when present) to prevent developpement of an inappropriate immune response and to improve the clinical response to reanimation treatment, in particular the respiratory parameters leading to a rapid improvement of clinical status. To that aim, the study investigates to compare a treatment using TPE plus usual treatments in intensive care unit (experimental arm) versus usual treatments in intensive care unit (routine arm) in a randomised trial.

Condition or Disease	Intervention/Treatment	Phase
Intensive Care Units ARDS, Human Covid19	Other: Therapeutic plasma exchange : 3 sessions in 3 consecutive days (day 1 to day 3) Other: Usual treatments in intensive care unit according to the current state of knowledge	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

132 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Assessment of Therapeutic Plasma Exchange to Improve Respiratory Function by Alleviating Cytokine Storm During Severe Covid-19 Infections Randomised Open-label Controlled Trial

Actual Study Start Date :

Apr 19, 2021

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TPE + usual treatments in intensive care unit according to the current state of knowledge. TPE + usual treatments in intensive care unit according to the current state of knowledge : 3 TPE sessions i.e. one per day during 3 consecutive days on day 1-3 (day 0 = inclusion Visit date)) + usual treatments in intensive care unit. Usual treatments of patients in intensive care unit with hyperinflammatory condition due to Covid-19 infection consist in supporting respiratory function, oxygen supplementation, non invasive ventilation, invasive ventilation, antibiotic, vasopressive support and corticosteroids (in absence of bacterial secondary infection)	Other: Therapeutic plasma exchange : 3 sessions in 3 consecutive days (day 1 to day 3) Therapeutic plasma exchange (TPE) ; 3 sessions in 3 consecutive days (Day 1 to Day 3) in intensive care unit in addition to usual treatments. Plasma removed is replaced by thawed fresh frozen plasma. Plasma blood volume exchanged : 1.2 Apheresis type: centrifugation Other: Usual treatments in intensive care unit according to the current state of knowledge Usual treatments of patients in intensive care unit with hyperinflammatory condition due to Covid-19 infection consist in supporting respiratory function, oxygen supplementation, non invasive ventilation, invasive ventilation, antibiotic, vasopressive support and corticosteroids (in absence of bacterial secondary infection)
Active Comparator: Usual treatments in intensive care unit according to the current state of knowledge Usual treatments of patients in intensive care unit with hyperinflammatory condition due to Covid-19 infection consist in supporting respiratory function, oxygen supplementation, non invasive ventilation, invasive ventilation, antibiotic, vasopressive support and corticosteroids (in absence of bacterial secondary infection)	Other: Usual treatments in intensive care unit according to the current state of knowledge Usual treatments of patients in intensive care unit with hyperinflammatory condition due to Covid-19 infection consist in supporting respiratory function, oxygen supplementation, non invasive ventilation, invasive ventilation, antibiotic, vasopressive support and corticosteroids (in absence of bacterial secondary infection)

Arm

Intervention/Treatment

Experimental: TPE + usual treatments in intensive care unit according to the current state of knowledge.

TPE + usual treatments in intensive care unit according to the current state of knowledge : 3 TPE sessions i.e. one per day during 3 consecutive days on day 1-3 (day 0 = inclusion Visit date)) + usual treatments in intensive care unit. Usual treatments of patients in intensive care unit with hyperinflammatory condition due to Covid-19 infection consist in supporting respiratory function, oxygen supplementation, non invasive ventilation, invasive ventilation, antibiotic, vasopressive support and corticosteroids (in absence of bacterial secondary infection)

Other: Therapeutic plasma exchange : 3 sessions in 3 consecutive days (day 1 to day 3)

Therapeutic plasma exchange (TPE) ; 3 sessions in 3 consecutive days (Day 1 to Day 3) in intensive care unit in addition to usual treatments. Plasma removed is replaced by thawed fresh frozen plasma. Plasma blood volume exchanged : 1.2 Apheresis type: centrifugation

Other: Usual treatments in intensive care unit according to the current state of knowledge

Usual treatments of patients in intensive care unit with hyperinflammatory condition due to Covid-19 infection consist in supporting respiratory function, oxygen supplementation, non invasive ventilation, invasive ventilation, antibiotic, vasopressive support and corticosteroids (in absence of bacterial secondary infection)

Active Comparator: Usual treatments in intensive care unit according to the current state of knowledge

Other: Usual treatments in intensive care unit according to the current state of knowledge

Outcome Measures

Primary Outcome Measures

Use of intubation and invasive ventilation (IV) between Day 0 (Inclusion Visit) and Day 10 [At day 10]
Proportion of patients requiring intubation between Day 0 and Day 10. Intubation use will be measured in both arms at Day 10.

Secondary Outcome Measures

Assess the adverse events according to CTCAE v5.0 [Throughout the study : Day 1 to Day 10 and to the end of the study (Day 60 +/- 2 days)]
Adverse events according to CTCAE v5.0 measured throughout the study, in both groups, including tolerance to TPEs in the experimental group over the course of the study sessions.
PaO2/FIO2 (Partial Pressure of Oxygen/Fraction of Inspired Oxygen) (mmHg) at day 4 after inclusion (PaO2/FiO2 is a usual parameter for assessing evolution of ARDS) [At Day 4]
PaO2/FIO2 (mmHg) at day 4 after inclusion. This parameter will be compared between day 4 and day 0.The change corresponds to an increase of PaO2/FIO2 ratio equal or superior than 20%. The proportion of patients with a PaO2/FiO2 change at Day 4 will be compared between both arms.
Percentage of patients weaned from non invasive ventilation [At day 10]
Percentage of patients weaned from high flow oxygen. This parameter is compared between both arms (experimental and control arms).
Survival at day 10 [At day 10]
Percentage of patients alive at day 10 after inclusion. This parameter is compared between both arms.
Survival at 2 months [At day 60 (+/- 2 days)]
Percentage of patients alive at 2 months after inclusion. This parameter is compared between both arms.
Percentage of patients without any increase in inflammatory parameters (analysis of C-reactive protein, Fibrinogen,D-Dimers, procalcitonin, Ferritin) [At day 4]
Percentage of patients without any increase in inflammatory parameters (analysis of C-reactive protein, Fibrinogen,D-Dimers, procalcitonin, Ferritin ) at day 4 compared to values at day 0. This parameter is compared between both arms.
Variation in cytokine and chemokine levels in the cytokine storm [At day 4]
Percentage of patients without any increase in cytokine or chemokine levels. Leucocyte and platelet cytokine or chemokine levels in ng/ml are assessed in both arms. Analysis of the entire panel of cytokines or chemokines defines an improvement or not. Comparison between both arms.
Percentage of patients with improved phenotype (decreased phenotype of exhausted cells) and improved function (improved proliferation) [At day 7]
Lymphocyte and NK (Natural Killer) labeling and analysis by flow cytometry at day 0 and day 7. Analysis of lymphocyte proliferation (after stimulation) at day 0 and day 7. Analysis of percentage of patients with improved phenotype (decreased phenotype of exhausted cells) and improved function (improved proliferation) ; this parameter is compared between both arms.
Percentage of patients with decreased platelet activation [At Day 4]
Phenotype of platelets and flow cytometry analysis performed before and after TPE or usual treatment. Percentage of patients with decreased platelet activation at day 4 ; this parameter is compared between both arms.
Percentage of patients with decreased platelet activation [At Day 7]
Phenotype of platelets and flow cytometry analysis performed before and after TPE or usual treatment. Percentage of patients with decreased platelet activation at day 7 ; this parameter is compared between both arms.
Change in anti-IFN auto-antibodies type I (α and ω) level [Day 0 and Day 4]
Change in anti-IFN auto-antibodies type I (α and ω) level at day 0 and day 4.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age > 18 years
Hospitalized for COVID-19 confirmed by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) or scanner
Patients with PaO2/FiO2 between 100 and 200 mmHg requiring non invasive ventilation or high flow oxygen
At least two biological results suggesting a cytokine storm or hyperinflammatory condition state among : C-reactive protéine (CRP)>50mg/L, Procalcitonin (PCT)>1µg/L, Fibrinogen>5g/L, D-dimer >1000ng/mL, Ferritin > 800ng/mL during the last 72 hours.
Treatment with corticosteroids (at least 2 intakes of dexamethasone 6 mg or equivalent with another form of corticosteroids)
Patient affiliated to a social security or similar scheme
Information and written consent from the patient or if not possible from a confident person

Exclusion Criteria:

Ventilated intubated patients
Patient with advanced cancer and without curative possibility
Bacterial or viral (HIV) infection explaining the worsening (the main reason)
Body Mass Index > 40
Impossibility to put a central venous catheter according to investigator's judgement
Severe hemodynamic instability with mean arterial pressure < 65 mmHg (whatever the noradrenaline dosage used)
Immunoglobulin A (IgA) deficiency with anti-IgA antibodies
Inclusion in another study that could interact with the Covidep study (investigator's judgement)
Patient under legal protection measure
Pregnant or breastfeeding women
In case of allergy to amotosalen (psoralens) or AI-FFP (Amotosalen Inactivated Fresh Frozen Plasma) , use Se-FFP (Secured Fresh Frozen Plasma)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Centre Hospitalier William Morey	Chalon-sur-Saône	France	71100
2	Hôpital Edouard Herriot	Lyon	France	69003
3	Hôpital Edouard Herriot	Lyon	France	69003
4	Hôpital Croix Rousse	Lyon	France	69004
5	Clinique de la Sauvegarde	Lyon	France	69337
6	Groupement Hospitalier Porte de Valence - Montélimar	Montelimar	France	26216
7	Hôpital Pitié Salpétrière - Assistante Publique des Hôpitaux de Paris	Paris	France	75013
8	Centre Hospitalier Lyon Sud	Pierre-Bénite	France	69310
9	Medipole Villeurbanne	Villeurbanne	France	69100